A key component to enhance immune-based strategies in cancer-bearing individuals is to increase the survival of effector T cells specific for tumor Ag(s), which leads to increased tumor-specific memory. In cancer-bearing hosts it is important to maintain high levels of tumor Ag-specific T cells, because it is difficult to eliminate every last tumor cell. In essence this creates an ongoing battle between the tumor cells and the immune system and it is essential that the immune system win for the host to survive. Learning how to tip the balance in favor of effector T cell survival will be an important strategy for enhancing immunity in cancer- bearing individuals. A recent clinical trial dramatically increased the survival of adoptively transferred tumor Ag-specific T cells in cancer patients and this increase in T cell survival correlated with increased clinical responses. Thus, understanding the mechanisms involved in the T cell survival pathway is crucial to developing new strategies aimed at potentiating tumor immunity in cancer patients. Our group has been studying the biologic function of the TNF-receptor family member, OX40, which has been shown by our group and others to enhance CD4 and CDS T cell survival leading to increased memory. In particular, we have shown that OX40 engagement in tumor-bearing hosts enhances anti-tumor immunity leading to destruction of tumors. We have found that mice cured of tumors through OX40 engagement have tumor-specific memory T cells capable of eliciting potent anti-tumor immunity upon adoptive transfer into naive mice. Therefore we propose to study the mechanism(s) involved with anti-OX40 mediated T cell survival in tumor-bearing hosts to further understand the link between increased tumor Ag-specific T cell survival and immune-mediated therapeutic efficacy. The specific aims of the grant application are as follows: 1) To understand the contribution that IL-12 makes to anti-OX40 enhanced tumor-specific T cell memory, 2) To elucidate the molecular basis for anti-OX40 enhancement of CD4 and CDS T cell survival, and 3) To determine clinically relevant ways to elicit synergy between anti-OX40 and innate cytokines to enhance tumor-specific T cell memory and destruction of tumors. The knowledge gained from this grant will help us design more effective ways to enhance tumor immunotherapy, and ultimately gain a greater understanding of anti-OX40-specific therapy. OX40-specific augmentation of the immune system has recently increased in relevance, because we have produced clinical grade anti-OX40 antibody and treated the first three cancer patients with this antibody as part of a phase I clinical trial.